Amides of benzoic acids with amine substituted piperidines

ABSTRACT

NOVEL COMPOUNDS ARE DESCRIBED AND CLAIMED, WHICH ARE AMIDES OF BENZOIC ACID WITH HETEROCYCLIC AMINES CARRYING A TERTIARY AMINO GROUP, TOGETHER WITH METHODS OF PRODUCING THE SAID COMPOUNDS. THE NOVEL COMPOUNDS ARE THERAPEUTICALLY ACTIVE IN THE TREATMENT OF PARKINSONISM.

United States Patent 3,634,410 AMIDES 0F BENZOIC ACIDS WITH AMINE SUBSTITUTED PIPERIDINES Ole Bent Tvaermose Nielsen, Vanlose, Denmark, Hans- Hasso Frey, Berlin, Germany, and Peter Werner Feit,

Gentofte, Denmark, assignors to Lvens kemiske Fabrik Produktionsaktieselskab, Ballerup, Denmark No Drawing. Filed Mar. 13, 1970, Ser. No. 19,474 Claims priority, application Gr/efiagt Britain, Mar. 19, 1969,

9 Int. Cl. C07d 29/28 US. Cl. Mil-293.64 7 Claims ABSTRACT OF THE DISCLOSURE Novel compounds are described and claimed, which are amides of benzoic acid with heterocyclic amines carrying a tertiary amino group, together with methods of producing the said compounds. The novel compounds aretherapeutically active in the treatment of parkinsomsm.

This invention relates to a series of hitherto unknown compounds of the general formula:

(CH2) n wherein R is a straight or branched C4 to C12 aliphatic hydrocarbon chain, unsubstituted or substituted with phenyl, phenoxy, or phenylthio, which R is directly attached to the benzene nucleus, or optionally may be attached to the benzene nucleus through a hetero atom selected from the group consisting of O and S; R is alkyl; R is a cycloalkyl radical with from 5 to 8 carbon atoms in the ring, or R together with (R can complete a heterocyclic ring which may be alkyl-substituted, n is an integer from 2 to 4, n is an integer from 1 to 5, and n is an integer from 1 to 3; to salts of the above compounds with pharmaceutically acceptable inorganic and organic acids; and to methods for the preparation of the compounds and their salts.

Whenever used in the statement above or in the description below, the term alkyl means lower-alkyl, including straight and branched aliphatic hydrocarbon chains with from 1 to 6 carbon atoms.

The compounds of the invention possess valuable pharmacological activities, e.g. displaying a favourable central anticholinergic action, and they are intended to be used in the treatment of patients suffering, for instance, from parkinsonism, including the post-encephalytic or arteriosclerotic parkinsonism and similar conditions.

As implied in the term, post-encephalytic parkinsonism refers to the appearance, as a sequence to encephalitis, of muscle rigidity and tremor, frequently along with spasmodic phenomena, whereas the term arteriosclerotic parkinsonism refers to the appearance, as a consequence of multiple cerebral vascular lesions, of difficulties of movements and fixity of posture and similar conditions occurring in the older age group, often combined with muscle rigidity while tremor is absent. The said disorders are chronic and progressive, and consequently all treatment is symptomatic and must be continued for long periods of time.

The known medication may comprise treatment with belladonna alkaloids, e.g. atropine, with amphetamine alone or in combination with belladonna alkaloids, with certain antihistamines or apomorphine, and similar unspecific medications, which may offer some degree of Patented Jan. 11, 1972 "ice symptomatic relief on tremor or spasmotic conditions, but no fixed dosage can be recommended, and ordinarily small amounts of the drug in question are used initially while larger doses are ultimately required whereby it may be necessary to approach the limit of tolerance and several toxic symptoms appear. Better results in the treatment of parkinsonism have been observed by using certain synthetic drugs as e.g. trihexyphenidyl (3- l-piperidyl l-phenyll-cyclohexyll-propanol) Caramiphen (2 diethylaminoethyl-l-phenyl-cyclopentane-l-carboxylate hydrochloride), or diethazide (diethylaminoethyl-N-dibenzoparathiazine) The action of trihexyphenidyl, resembles that of atropine in particular as far as the antispasmotic properties are concerned, whereas some of the undesired effects of atropine are weaker, but still the peripheral parasympatholytic action of trihexyphenidyl must be considered an undesired effect in the treatment of parkinsonism where in particular the central action is important.

As far as the chemical constitution is concerned, the compounds of the present invention are widely different from the drugs mentioned above, and it has surprisingly been found that the compounds of Formula I exert a favourable specific therapeutic action in the treatment of all forms of parkinsonism.

According to experiments, the preferred compounds for the treatment of parkinsonism are those of Formula I in which R is a C5 to C7 aliphatic hydrocarbon chain attached to the benzene nucleus through one of the hetero atoms 0 and S the integers in and n being within the limits from 2 to 3, and from 2 to 4 respectively, and in which R is a C1 to C2 aliphatic group, and R is a C4 to C7 cycloalkyl group, or in which R and R together with the N atom form a heterocyclic ring.

In particular, however, the preferred compounds are those in which R has the meaning defined above and is in the 4-position in the benzene nucleus, and in which R and R together form an unsubstituted or alkyl-substituted pyrrolidino, piperidino, or hexamethyleneimino group.

Thus, the compound l-(4-n-hexyloxybenzoyl)-4-(piperidinoethyl)-piperidine hydrochloride, among a series. of related compounds, displayed a promising central anticholinergic activity, while its peripheral parasympatholytic effects were comparably weak. Its antagonistic effects against the tremorgenic action of tremorine and oxotremorine, which is considered to be the most predictive pharmacological model of parkinsonism, were two to five times stronger than those of trihexyphenidyl, being at present the drug of choice in the treatment of parkinsonism. Furthermore, the central effects of oxotremorine (tremor) were inhibited with lower doses than the peripheral effects (salivation) which as mentioned above is highly desirable for antiparkinsonism drugs.

Experiments in higher animals further confirmed the I favourable weak peripheral anticholinergic action of the compounds of the invention.

The acute oral toxicity of e.g. l-(4-n-hexyloxybenzoyl)- 4-(piperidinoethyl)-piperidine HCl expressed in LD (mice) is 470 mg./kg., which may be considered low when compared to the degree of activity in the antiparkinson test in which an effect could be observed with amounts of the order 0.5 to 2.0 rug/kg.

The chronical toxicity was studied in animal experiments in which the test animals were rats (Leo Wistar strain). The compounds were administered orally each day during a period of six months in various doses, in one animal section in a daily dose of 50 mg./ kg.

Even in this latter section no adverse clinical signs were seen, and no adverse changes in bodyweight could be demonstrated. The investigation comprises a full haematological and pharmacological analysis of the animals, and after post-mortem examinations no abnormalities were demonstrated.

Pharmaceutical compositions containing a compound of the invention also constitute part of this invention. In these compositions, the proportion of therapeutically ac tive material to carrier substances and auxiliary agents can vary between 0.04 and depending upon the form of pharmaceutical presentation.

The compositions in question can be worked up to pharmaceutical forms of presentations, such as tablets, pills, dragees and suppositories, or the compositions can be filled in medical containers, such as capsules or ampoules or, as far as mixtures or elixirs are concerned, they may be filled into bottles and similar containers.

Pharmaceutical inorganic or organic, solid or liquid carriers suitable for enteral and parenteral administration can be used to make up the compositions, water, gelatine, lactose, starch, magnesium stearate, talc, vegetable and animal oils and fats, benzyl alcohol, gums, polyalkylene glycol and similar other known carriers for medicaments being suitable as carriers, while stabilizing agents, wetting or emulsifying agents, salts for varying the osmotic pressure or buffers for securing an adequate pH-value of the compositions can be used as auxiliary agents.

In the compositions, the compounds of Formula I may be present as such or in the form of one of their salts with a pharmaceutically acceptable inorganic or organic acid, as for instance a hydrochloride, hydrobromide, hydroiodide, sulphonate, sulphate, phosphate, sulphamate, tartrate, maleate, citrate, acetate, succinate, or benzoate.

An object of the invention also resides in the selection of a dose of the compounds of Formula I which can be administered so that the desired activity is achieved without simultaneous secondary eflects.

In clinical practice, the compounds of the invention may conveniently be administered by injection, preferably once per day, and in amounts corresponding to a total daily dose of from 0.1 to mg.

In particular, however, the compounds may be given by the oral route in the form of tablets and the like, or in the form of a mixture or elixir, one to four times per day and in a total daily dose of from 0.2 to 50 mg, always with due regard to the condition of the patient and in accordance with the prescription of the medical practitioner.

The compounds of the invention may conveniently be administered in dosage units containing not less than 0.5 mg, and preferably from 1 to 25 mg. of the active compound.

By the term dosage unit is meant a unitary, i.e. a single dose capable of being administered to the patients, and which may be readily handled and packed remaining as a physically stable unit dose comprising either the active material as such or as a mixture of it with a solid or liquid pharmaceutical diluent or carrier.

If the compound is to be injected, a sealed ampoule, a vial or a similar container may be provided, containing a parenterally acceptable aqueous or oily injectable solution or dispersion of the active material as a dosage unit as mentioned above.

When in the form of tablets, pills, and the like, the dosage unit may contain from 0.5 to 25 mg., and preferably contains from 1 to 10 mg. of the active compound which is readily absorbed when orally administered.

When in the form of injectable preparation, the dosage unit preferably contains from 0.1 to 25 mg. of the active compound.

When the active compound is administered as a mixture or elixir, this pharmaceutical preparation may preferably contain 0.5 to 10 mg. per cc. The dosage units aforesaid also constitute part of the present invention.

It is still another object of the invention to provide 4 a method of producing the compounds represented by the general Formula I.

In the method of the invention, a compound of the general formula C C-COY wherein R has the meaning hereinbefore defined, is reacted with a compound of the general formula (III) wherein R R 12, n and 11 have the meanings hereinbefore defined, and the terms COY and XN in Formulae II and III shall mean radicals capable of reacting with each other to form a CON bridge, the resulting compound being recovered as such or as one of its salts with an acid.

Most of the starting substances of the Formulae II and III are known compounds, the preparation of which is described in the literature,'or they may, if not known, be prepared in analogy with the known compounds.

Thus e.g. certain functional reactive derivatives of the alkylthiobenzoic acids used as starting substances in the method are hitherto unknown compounds which may be prepared in a Sandmeyer reaction in which the diazotized mor p-aminobenzoic acid is reacted with an alkalimetal xanthogenate to form the corresponding xanthate, which is hydrolyzed and alkylated in one step by reacting with an alkyl halide under alkaline conditions resulting in the desired alkylthiobenzoic acid.

The radical COY of the starting substances of Formula II stands for various reactive groups corresponding to starting substances as for instance an acid halide, such as an acid chloride or bromide, an anhydride, a mixed anhydride with an alkyl-carbonic acid, such as isobutyl-carbonic acid, a carboxylic acid, an inorganic acid or a sulphonic acid; or a radicalobtained by reacting the corresponding free acid with a carbodiimide or N',N- carbonyldiimidazole 'or a similar functioning compound.

In the Formula III, X may preferably be hydrogen. The process of the invention is conveniently performed in the presence of an inert solvent and, if in the absence of water, at room temperature for a period of time necessary to accomplish the desired degree of conversion, commonly by standing overnight. In this embodiment, equimolar amounts or an excess of the compound of Formula II may appropriately be employed in order to form e.g. the hydrogen halide of compounds of Formula I directly in the reaction mixture.

In another embodiment, the reaction is performed in the presence of an inert solvent, preferably immiscible with water, and at temperatures on or below 0 C. while any acid component formed during the reaction, e.g. a hydrogen halide, is continuously removed by adding an aqueous solution of a base, e.g. an alkali metal hydroxide. In this embodiment, the starting substances are used in equivalent amounts, or in substantially equivalent amounts, and the reaction may be completed Within a few hours.

After complete reaction, the desired compound is readily recovered from the organic phase, if necessary after removal of a possible excess of the starting substance of Formula II by extraction with an aqueous solution of an inorganic base, by evaporation of the organic solvent, and recrystallization of the residue, or the compound may be isolated as a salt with an acid by neutralizing the base, in a suitable solvent or mixture of solvents, with a view to the precipitation or crystallization of the salt.

The invention will now be illustrated by the following non-limiting examples.

EXAMPLE 1 4-n-hexylthiobenzoic acid To a solution of 4-aminobenzoic acid (32 g.), sodium nitrite (18.8 g.), and sodium hydroxide (11 g.) in water (150 ml.), concentrated hydrochloric acid (50- ml.) was slowly added while stirring vigorously at 50 C. After the addition was completed, the stirring was continued further for 1 hour at O5 C. The cooled diazonium-solution was filtered and slowly added to a solution of potassium xanthogenate (62.5 g.) and sodium carbonate (87.5 g.) in water (250 ml.) at 6570 C. while stirring vigorously. The mixture was stirred at 6570 C. further for 1 hour. After cooling, the mixture was carefully acidified with concentrated hydrochloric acid (150 ml.). The precipitated material was filtered off, washed with water, and dissolved in sodium hydroxide solution (500 ml.). The flask was filled with nitrogen, closed, and left overnight. n-Hexylbromide (85 g.) was added, and the mixture was refluxed for 3 hours. The resulting mixture was poured into concentrated hydrochloric acid (200 ml.)/ice (about 200 g.), and the precipitate was filtered off and washed with water. After drying, 22 g. of crude 4-n-hexylthiobenzoic acid with a melting point of 89-93 C. was obtained. A sample repeatedly recrystallized from cyclohexane had a melting point of 9698 C.

EXAMPLE 2 4- (4-phenylbutoxy) -b enzoic acid A solution of ethyl 4-hydroxy benzoate (11 g.), 4- phenylbutyl bromide (17 g.), and sodium (1.53 g.) in ethanol (50 ml.) was refluxed for 20 hours and was then evaporated in vacuo. 4 N sodium hydroxide ml.) was added to the residue, and the mixture was heated on a steam bath for 5 hours. After cooling, the resulting solution was acidified with concentrated hydrochloric acid (15 ml.). The precipitated material was collected by filtration and washed with water. After drying, 4-(4-phenylbutoxy)-benzoic acid with a melting point of 128131 C. was obtained. A once repeated recrystallization from aqueous ethanol raised the melting point to ISO-132 C. By substituting equimolar amounts of 2-n-butylthioethylchloride for the 4-phenylbutylbromide in the above proce dure, 4-(2-n-buty1thioethoxy)-benzoic acid (M.P. 9597) was obtained.

EXAMPLE 3 4-piperidinomethyl-piperidine dihydrochloride hydrate To a stirred mixture of piperidine (12 g.), potassium carbonate (28 g.), and methanol (100 ml.), 4-chloromethylpyridine hydrochloride (16.4 g.) was added in portions. The mixture was stirred at room temperature for further 2 hours and was then evaporated in vacuo. The residue was treated with 2 N sodium hydroxide (25 ml.), and the separated oil was extracted with diethyl ether. The organic phase was dried (MgSO and distilled. 4- piperidinomethylpyridine with a boiling point of 126 126.5 C. at 9 mm. Hg was obtained. This material was dissolved in a mixture of methanol (75 m1.) and 3 N hydrochloric acid ml.) and was hydrogenated after addition of Pt0 (0.5 g.). The hydrogen uptake was complete within 3.5 hours. The catalyst was removed by filtration, and the filtrate was evaporated in vacuo. The crystalline residue was triturated With acetone and collected by filtration. After drying, 4-piperidinomethylpiperidine dihydrochloride hydrate with a melting point of about 260 C. was obtained. Recrystallization from ethanol raised the melting point to 265-266 C.

EXAMPLE 4 4- [2- (4-methylpiperidino -ethyl] -piperidine dihydrochloride A mixture of 4-vinylpyridine (25 g.) 4-methylpiperidine (35.4 g.) and acetic acid (3.5 ml.) was heated on a steam bath for 24 hours. 4 N sodium hydroxide (25 ml.)

was added to the cooled mixture, and the separated oil was extracted with diethyl ether. The organic phase was dried (MgSO and distilled. 4-[2-(4-Methylpiperidino)- ethylJ-pyridine with a boiling point of 15l154 C. at 9 mm. Hg was obtained. This material was dissolved in a mixture of methanol (230 ml.) and 4 N hydrochloric acid (130 ml.) and was hydrogenated after addition of PtO (1.0 g.). The hydrogen uptake was complete within 20 hours. The catalyst was removed by filtration, and the filtrate was evaporated in vacuo. The crystalline residue was triturated with acetone and was collected by filtration. After drying, 4-[2-(4-methylpiperidino)-ethyl]- piperidine dihydrochloride with a melting point higher than 290 C. was obtained. By substituting equimolar amounts of 3-methylpiperidine or N-methyl-cyclohexylamine for the 4-methylpiperidine in the above procedure, 4 [2- B-methylpiperidino -ethyl] piperidine dihydrochloride (M.P. 267-269 C.) and 4-(2-N-methylcyclohexylamino ethyl) piperidine dihydrochloride (hygroscopic) were obtained, respectively.

EXAMPLE 5 1-(4-n-hexyloxybenzoyl)-4-(2-piperidinoethy1)- piperidine hydrochloride A solution of 4-n-hexyloxybenzoyl chloride (5.0 g.) in methylene chloride (25 ml.) was slowly added to a mixture of 4-(2-piperidinoethyl)-piperidine dihydrochloride (5.4 g.), methylene chloride (25 ml.), and 2 N sodium hydroxide ml.) at 0-5 C. while stirring. After the addition was complete, the stirring was continued for further 4 hours. The organic layer was separated, washed with brine, dried (MgSO and evaporated in vacuo. The remaining material was dissolved in diethylether (50 ml.) and acidified with dry ethanolic hydrochloric acid. The precipitated oily material was crystallized from isopropanol/diethylether. After drying and recrystallization from acetone, 6.3 g. of 1-(4-n-hexyloxybenzoyl)-4- (2-piperidinoethyl)-piperidine hydrochloride with a mel ing point of 197.5198.5 C. was obtained.

EXAMPLE 6 By substituting equimolar amounts of respectivelv 4-n-propyloxybenzoyl chloride, 4-isopropyloxybenzoyl chloride, 4-n-butyloxybenzoyl chloride, 4-sec.-butyloxybenzoyl chloride, 4-isobutyloxybenzoyl chloride, 4-isoamyloxybenzoyl chloride, 4-n-heptyloxybenzoyl chloride, 4-n-octyloxybenzoyl chloride, 3-n-propyloxybenzoyl chloride,

' 3-n-butyloxybenzoyl chloride,

1- (4-isobutyloxybenzoyl) -4- (Z-piperidinoethyl -piperidine hydrochloride (M.P. 189-191 C.)

1-(4-isoamyloxybenzoyl)-4- (2-piperidinoethyl)- piperidine hydrochloride (M.P. 207-209 C.)

1-(4-n-heptoxybenzoyl)-4-(2-piperidinoethyl) -piperidine hydrochloride (M.P. 197-199 C.

1- (4-n-octyloxybenzoyl)-4-(2-piperidinoethyl)-piperidine hydrochloride (M.P. 1935-1995 C.

1-( 3-n-propylox'ybenzoyl) -4-(2.-piperidinoethyl)-piperidine hydrochloride semihydrate (M.P. 156.5-15 8.5

1-(3-n-butyloxybenzoyl)-4-(2-piperidinoethyl)-piperidine hydrochloride (M.P. 135.5-1365 C.

1- 3-n-amyloxybenzoyl -4- (Z-piperidinoethyl) -piperidine hydrochloride (M.P. 124-126 C.

1- 3-n-hexyloxybenzoyl -4- (piperidinoethyl) -piperidine hydrochloride (MP. 13 5-13 6 C.)

1- (4-n-hexylthiobenzoyl -4'- (Z-piperidinoethyl) -piperidine hydrochloride (M.P. 166-168 C.),

1- (4-n-butylbenzoyl)4-(2-piperidinoethyl)-piperidine hydrochloride (MAP. 1715-1725 C.

1- 4-n-pentylbenzoyl -4- 2-piperidinoethyl) -piperidine hydrochloride (170.5-172 C.)

1-(4-n-hexylbenzoyl)-4-(Z-piperidinoethyl)-piperidine hydrochloride (M.P. 1725-1735 C.)

1- [4- (2-phenylethoxy)-benzoyl]-4- (2-piperidinoethyl) -piperidine hydrochloride (M.P. 190-1915 C.)

1-[4-(3-phenylpropoxy)-benzoyl]4- (2-piperidinoethyl) -piperidine hydrochloride (M.P. 204-205 C.),

l- [4- (4-phenylbutoxy) -benzoyl] -4- (Z-piperidinoethyl) piperidine hydrochloride MP. 8.5-1 60 C.)

1- [4- 2-phenoxyethoxy) -benzoyl] -4- (2-piperidinoethyl)-piperidine (M.P. 103-106 C.

1-[4- (Z-n-butylthioethoxy)-benzoyl]-4- (Z-piperidinoethyl) -piperidine hydrochloride (M.P. 161-163 1- (4-n-heptylbenzoyl) -4- 2-piperidinoethyl -piperidine hydrochloride (M.P. 173-1735 C.), and

1- 4-n-octylbenzoyl -4- 2-piperidinoethyl -piperidine hydrochloride (M.P. 177-179 C.),

respectively, were obtained.

EXAMPLE 7 By substituting equimolar amounts of respectively 4-piperidinomethyl piperidine dihydrochloride,

4-(3-piperidinopropyl)-piperidine dihydrochloride,

4- (2-n-methylcyclohexylaminoethyl) -piperidine dihydrochloride,

4-(2-morpholinoethyl) -piperidine dihydrochloride,

3-(piperidinomethyl)-piperidine dihydrochloride,

4- 2-pyrrolidinoethyl -piperidine dihydrochloride,

4-(2-hexamethyleneiminoethyl)-piperidine dihydrochloride, 2

4- [2- 3-methylpiperidino -ethyl] -piperidine dihydrochloride, or 4-[2-(4-methylpiperidino)-ethyl]-piperidihydrochloride, for the 4-(2-piperidinoethyl)-piperidine dihydrochloride in the procedure described in the Example 5 above,

1- 4-n-hexyloxybenzoyl -4-piperidinomethyl piperidine hydrochloride (M.P. 199-2005 0.),

1- (4-n-hexyloxybenzoyl -4- 3-piperidinopropyl piperidine hydrochloride (M.P. 147-149 C.),

1-(4-n-hexyloxybenzoyl)-4-(2-n-methylcyclohexylaminoethyl)-piperidine hydrochloride (M.P. 194- 195 C.),

1- 4-n-hexyloxybenzoyl -4- (2-morpholinoethyl) piperidine hydrochloride (M.P. 1855-l87 C.),

1- (4-n-hexyloxybenzoyl-3- (piperidinomethyl) -piperidine hydrochloride (M.P. 149-151 C.),

1- (4-n-hexyloxybenzoyl -4- 2-pyrrolidinoethyl piperidine hydrochloride (M.P. 14'25-144.5 C.),

1- (4-n-hexyloxybenzoyl) -4- (2-hexamethyleneimino- 8 ethyl)-piperidine hydrochloride (M.P. 1665-1685 C.),

1- (4-n-hexyloxyb enzoyl) -4- [2- 3 -methylpip eridino ethylJ-piperidine hydrochloride (M.P. 1745-177 C.), and

1- 4-n-hexyloxybenzoyl) -4-( [2- (4-methylpiperidino) ethyl]-piperidine hydrochloride (M.P. 178-180 C.),

respectively, were obtained.

EXAMPLE 8 By using the procedure described in the Example 5 above and substituting equimolar amounts of 4-n-aniyl oxybenzoyl chloride for the 4-n-hexyloxybenzoyl chloride and 48% hydrobromic acid for the ethanolic hydrochloric acid, 1-(4-n-amyloxybenzoyl)-4-(2-piperidinoethyl) piperidine hydrobromide (M.P. 192.5-l94 'C.) was obtained.

' EXAMPLE 9 I Tablets containing 5 mg. of the active compound and being of the following composition, were prepared as de scribed below:

Mg. 1 (4-m-hexyl0XybenZoyD-4-(piperidinoethyl)-piperidine hydrochloride Lactose 69 Starch 57 Gelatine 2 Talc 9 The calculated amount of active compound, lactose, and starch were mixed, granulated with a soltuion of gelatine in water, and dried. After sifting, the calculated amount of talc was added, and the tablets were made by means of'a. 17 mm. punching die which provided tablets weighing 142 mg. each corresponding to 5 mg. of the active compound per tablet.

What we claim is:

1. A piperidine compound of the formula References Cited UNITED STATES PATENTS 3,468,892 9/1969 Tomcufcik et al. 260,293

HENRY R. JILES, Primary Examiner G. T. TODD, Assistant Examiner US. Cl. X.R. 

